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Supplementary Tables from Integrated Screens Identify CDK1 as a Therapeutic Target in Advanced Gastrointestinal Stromal Tumors

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posted on 2023-03-31, 04:47 authored by Xiaojing Lu, Yuzhi Pang, Hui Cao, Xiaoxiao Liu, Lin Tu, Yanying Shen, Xiaona Jia, Jen-Chieh Lee, Yuexiang Wang

Supplementary Tables 1-5. Supplementary Table S1. Clinicopathologic classification and CDK1 expression for the discovery GIST cohort (n=43). Supplementary Table S2: List of all 14280 genes expressed in GIST. Supplementary Table S3: List of 568 genes with a higher expression level in advanced GIST than in early-stage GIST. Supplementary Table S4: Ranked CRISPR scores for each gene from a genome-wide CRISPR screen in GIST430/654 cells. Supplementary Table S5: Clinicopathologic classification and CDK1 expression for the validation GIST cohort (n=92).


National Natural Science Foundation of China

National Key R&D Program of China

Shanghai Science and Technology Commission

Tissue Microenvironment and Tumor of Chinese Academy of Sciences

Brigham and Women's Hospital

Harvard Medical School

Klingenstein Third Generation Foundation

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Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumor (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with advanced GIST. Polyclonal emergence of KIT/PDGFRA secondary mutations is the main mechanism of imatinib progression, making it challenging to overcome KIT/PDGFRA-inhibitor resistance. It is unclear whether there are other therapeutic targets in advanced GIST. Using genome-wide transcriptomic profiling of advanced versus early-stage GIST and CRISPR knockout functional screens, we demonstrate that CDK1 is frequently highly expressed in advanced GIST but not in early-stage GIST across three patient cohorts. High expression of CDK1 was associated with malignancy in GIST. CDK1 was critically required for advanced GIST, including imatinib-resistant GIST. CDK1 ablation led to robust proliferation inhibition. A mass spectrometry-based proteomics screen further revealed that AKT is a novel substrate of CDK1 kinase in GIST. CDK1 bound AKT and regulated its phosphorylation, thereby promoting GIST proliferation and progression. Importantly, a pharmacologic inhibitor of CDK1, RO-3306, disrupted GIST cell proliferation in CDK1 highly expressed GIST but not in CDK1-negative GIST cells and nontransformed fibroblast cells. Treatment with RO-3306 reduced tumor growth in both imatinib-resistant and imatinib-sensitive GIST xenograft mouse models. Our findings suggest that CDK1 represents a druggable therapeutic target in GIST and warrants further testing in clinical trials. These findings propose CDK1 as a novel cell-cycle–independent vulnerability in gastrointestinal stromal tumors, representing a new therapeutic opportunity for patients with advanced disease.

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